Japanese Journal of Clinical Oncology Advance Access originally published online on June 16, 2006
Japanese Journal of Clinical Oncology 2006 36(7):432-438; doi:10.1093/jjco/hyl041
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© 2006 Foundation for Promotion of Cancer Research
Efficacy of Up-Front Treatment with a Double Stem Cell Transplantation in Multiple Myeloma
Catholic Hematopoietic Stem Cell Transplantation Center, St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
For reprints and all correspondence: Chang-Ki Min, Division of Hematology, Department of Internal Medicine, St Mary's Hospital, #62 Youido-Dong, Youngdungpo-Gu, Seoul 150-713, South Korea. E-mail: ckmin{at}catholic.ac.kr
Received December 30, 2005; accepted March 27, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: We report the outcome of 53 patients with multiple myeloma (MM), who received autologous stem cell transplantation (ASCT) from April 1996 to September 2004 at our institution and who survived for more than 3 months after the transplant.
Methods: Following the first ASCT, 36 patients underwent an up-front second SCT, which consisted of either an ASCT (n = 24) or a reduced-intensity conditioning allogeneic stem cell transplant (RIST) (n = 12). Seventeen patients were given maintenance treatment.
Results: Seventy-seven percent of the patients (n = 41) showed an objective response to the initial therapy prior to the first ASCT. Overall, 60.4% (32 out of 53) and 32.1% (17 out of 53) of the patients had a complete response (CR) and partial response (PR) after the first ASCT, respectively. At the time of analysis, 34 patients (64.2%) were still alive. With a median follow-up of 32 months (range 9–98), the estimated progression-free survival (PFS) and overall survival (OS) at 5 years were 17.0 and 34.9%, respectively. Multivariate analysis revealed that the second SCT, normal hemoglobin and <50% marrow plasma cells were associated with an improved PFS. A second SCT, CR to the first SCT, female gender and an absence of advanced bone lesions were associated with a better OS.
Conclusions: A second SCT is the most significant factor for an improved PFS and OS after the first ASCT (P < 0.001, respectively). Up-front double SCT is needed to improve the OS and PFS in patients with MM.
Key Words: multiple myeloma • tandem stem cell transplantation • reduced-intensity allogeneic transplantation • autologous stem cell transplantation
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The use of autologous stem cell transplantation (ASCT) after intensive chemotherapy or chemo-radiotherapy is part of the initial treatment plan for patients with multiple myeloma (MM). Although a large randomized trial demonstrated superior response rates and survival compared with the conventional therapy, the disease eventually recurs and relapse remains the main reason for treatment failure after ASCT (1).
Many studies have evaluated combined ASCT with a subsequent transplant using either an autograft or allograft in an attempt to prolong the duration of the response (2–5). The achievement of a complete response (CR) is the crucial factor affecting the outcome after ASCT. The higher CR rates after the second transplant compared with the first ASCT provide the conceptual basis for a tandem transplant. Recent results from an IFM94 trial showed that a double ASCT is superior to a single ASCT, at least in patients who do not achieve a 90% response after one transplant (6). An allogeneic SCT with a dose-reduced conditioning regimen after an ASCT as part of the initial therapy might be a feasible and highly effective approach for patients with MM (4,5).
The aims of this study were to determine the prognostic parameters, associated with the outcome of patients with MM who had received an ASCT, and to evaluate the efficacy of a double SCT. A second SCT was found to be the most powerful factor that correlates with improved event-free and overall survival rates in MM patients receiving their first ASCT. In addition, there was no difference in the outcome of the second transplant between an autograft vs allograft. In order to prolong the duration of the response, a double SCT should be encouraged after the first ASCT.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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INCLUSION AND DIAGNOSTIC CRITERIA
From April 1996 to September 2004, 57 patients with MM, who were younger than 65 years (median 52, range: 32–62), underwent an ASCT followed by high-dose therapy. Four patients, who died from disease progression or non-relapsing mortality within 3 months after the ASCT, were excluded from the analysis. Fifty-three patients who survived for more than 3 months after the ASCT were analyzed. A diagnosis of MM was based on the criteria of the Chronic Leukemia-Myeloma Task Force (7).
INITIAL CHEMOTHERAPY AND STEM CELL COLLECTIONS
The majority of patients (49 patients, 92.5%) initially received four cycles of infusional chemotherapy with vincristine (0.4 mg/day on days 1–4), doxorubicin (9 mg/m2/day on days 1–4) or epirubicin (13.5 mg/m2/day on days 1–4) and dexamethasone (40 mg/day on days 1–4, 9–12 and 17–20). The remaining four patients had a combination of vincristine (0.03 mg/kg/day on day 1), BCNU (1.0 mg/kg/day on day 1), melphalan (0.25 mg/kg/day on days 1–4), cyclophosphamide (10 mg/kg/day on day 1) and prednisone (1.0 mg/kg/day on days 1–7) as their initial therapy.
The stem cells were collected after the initial administration of cyclophosphamide 1.5–2.0 g/m2 per day for 2 consecutive days. This was followed by the subcutaneous administration of filgrastim (granulocyte-colony stimulating factor, G-CSF) at 10 µg/kg, beginning on the day the absolute neutrophil count (ANC) was <0.5 x 109/l after chemotherapy. G-CSF was continued until the collection was complete. Apheresis was performed once the total number of CD34+ cells exceeded 20 x 106/l. The target for the apheresis procedure was either 5 x 108 mononuclear cells/kg or 5 x 106 CD34+ cells/kg.
HIGH-DOSE THERAPY AND HEMATOPOIETIC STEM CELL TRANSPLANTATION
For the first ASCT, the conditioning regimens consisted of either melphalan alone (200 mg/m2) in 50 patients (94%) or melphalan 140 mg/m2 and total body irradiation (TBI) (1000 cGy over a 3-day period) in 3 patients. Due to referral reasons, the patients preference or the availability of HLA-matched siblings in the trials, 36 patients received either a second ASCT (n = 24) or a tandem reduced-intensity conditioning allogeneic stem cell transplant (RIST) from HLA-matched siblings (n = 12) while 17 patients were continued on maintenance treatment including IFN
, prednisone or thalidomide. Patients usually decided to undergo the second SCT on the basis of financial status, because our national insurance system only covered the first one. Out of 36 patients who received second SCT, all patients who had a HLA-matched donor underwent a RIST. Two patients were treated with thalidomide (100 mg/day) for 2 years as a maintenance treatment. All patients undergoing tandem SCT received their first ASCT after preparation with melphalan alone. For those patients undergoing ASCT as a second transplant, melphalan (140 mg/m2) + TBI (1000 cGy) were used as the conditioning regimen. Patients undergoing RIST received fludarabine (30 mg/m2/day) for 4 days and melphalan 70 mg/m2/day on two consecutive days before infusing the G-CSF mobilized peripheral blood mononuclear cells. The patients received cyclosporine A (CsA) and mycophenolate mofetil (MMF) as the GVHD prophylaxis (8). CsA was administered intravenously at a dose of 3 mg/kg as a continuous infusion from day –1. Subsequently, when the patients could tolerate an oral intake, they received CsA orally at a dose of 6 mg/kg/day in 2 divided doses until day +60. Subsequently, the patients showing either 100% donor complete chimerism or acute graft-versus-host disease (GVHD) (
grade 2) were given continued CsA until day +180 after RIST. CsA was tapered off until day +120 in patients with either mixed chimerism or residual myeloma on day +60. MMF was withdrawn until day +40 after RIST. If the patients still showed mixed chimerism or residual myeloma after CsA withdrawal, a monthly increasing dose of donor lymphocyte infusion (DLI; 1 x 106, 5 x 106 and 1 x 107/kg) was added. Acute GVHD was graded on a four-point scale (I indicates mild disease, and IV severe disease) (9), and chronic GVHD was classified as being either limited or extensive, as previously described (10). All patients were treated in HEPA-filtered rooms using standard reverse isolation procedures. Oral prophylactic antibiotics were administered to all the patients. As soon as fever had developed, the oral antibiotics were discontinued and broad-spectrum intravenous antibiotics were administered. All the blood components were irradiated in order to prevent transfusion-related GVHD.
DEFINITION OF RESPONSE
Responses were classified using the standard criteria (11). Immunoelectropheresis (IEP) was used to determine the presence of serum and/or urine monoclonal immunoglobulin. The marrow examination included staining to demonstrate the light-chain or non-secretory disease. A CR was defined by the presence of <5% polyclonal plasma cells in the bone marrow (BM) and an absence of monoclonal protein in the serum or urine by IEP. A partial response (PR) was defined as the presence of a 50% decrease in the serum and/or urine monoclonal protein and <10% monoclonal plasma cells on the BM biopsy. Stable disease (SD) was defined as a <50% reduction in the paraprotein level. Progressive disease (PD) was defined as the re-appearance of the serum and/or urine monoclonal protein in those patients with a CR, or >25% increase in the serum and/or urine monoclonal protein from the lowest value observed for those patients with a PR. The objective response rate (ORR) included both CR and PR.
STATISTICAL METHODS
The aim was to determine which factors are important for improving the progression-free survival (PFS) and overall survival (OS) after the first ASCT. The duration of the PFS was calculated for all patients from the date of the first ASCT to the time of progression, relapse or death. The OS was defined as the time from the first SCT to the date of death or the last follow-up. Kaplan–Meier curves for the PFS and OS were plotted and compared using a log-rank test. A cutoff date of 31 May 2005 was used for survival analysis. The factors of interest in the patient groups were compared. Preliminary univariate analyses were used to identify the factors that could be used to build a Cox proportional hazard regression model for the PFS and OS rates. The markers of the tumor burden and/or disease activity including ß2-microglobulin, the degree of bone marrow plasmacytosis, hemoglobin, serum M-protein and calcium levels were analyzed. The proportion of patients with a given characteristic was compared using a chi-square test or Fisher's exact test. The differences in the means of the continuous measurements were examined using a Student's t-test and were checked using a Mann–Whitney U-test.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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BASELINE CLINICAL AND LABORATORY FEATURES
Table 1 shows the baseline characteristics of the 53 patients. Thirty-one were male (58.5%), and the median age was 51 years (range, 32–62). Most patients had a high tumor burden, with 49 patients (92.5%) having Durie–Salmon stage III. Forty-three percent patients had advanced bone disease. Only four patients had a creatinine >2.0 mg/dl at transplant, whereas 38, 24, 3.5 and 21% of the patients were immunoglobulin G (IgG), IgA, IgM and light-chain disease, respectively. The median duration from the initial therapy to the first SCT was 7 months (range 5–13). Seventy-five percent of patients (n = 41) had obtained an objective response to the initial chemotherapy at the time of the first ASCT. Sixteen patients were in CR (30.2%), 25 in PR (47.2%) and 12 in SD (22.6%).
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RESPONSE TO THE FIRST ASCT AND THE CHARACTERISTICS OF THE SECOND TRANSPLANT
Table 2 details the characteristics of the first ASCT. The source of the hematopoietic stem cells was peripheral blood for all patients, who received an average of 9.5 (range 4.2–25.0) x 106 CD34+ cells/kg. There were no engraftment failures. The overall median times to achieve an ANC >0.5 x 109/l and a platelet count >20 x 109/l for three consecutive days were 12 days (range 9–20) and 15 days (range 12–28), respectively. The overall ORR after the first ASCT was 92.5%; 32 out of 53 patients (60.4%) obtained a CR and 17 out of 53 (32.1%) had a PR. There was a 94% ORR with patients who received the second transplant and an 88% ORR with those who received the maintenance treatment (P = 0.1).
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The median time from first ASCT to the second transplant was 5 months (range, 3.5–10). The most common post-transplant toxicity encountered included nausea, diarrhea, mucositis and neutropenic fever. The post-SCT hospital stay and the median time to ANC and platelet recovery were similar in the two groups. Every patient with RIST was shown to be ‘fully donor’ by the analysis of chimerism. At a median follow-up of 31.5 and 30 months, 11 out of 24 patients (45.8%) relapsed in the ASCT group while 4 out of 12 (33.3%) relapsed in the RIST group. Three out of four patients (75%) who relapsed after RIST had extramedullary plasmacytomas without BM relapse. There were 4 cases (33.3%) of grades II–IV acute GVHD and finally 2 cases of limited and 4 cases of extensive chronic GVHD. Three patients with DLI developed extensive chronic GVHD.
SURVIVAL AND PROGNOSTIC FACTORS
Thirty-four patients (64.2%) were still alive at the time of the analysis. The median follow-up from the first ASCT for those patients alive at the last follow-up was 32 months (range 9–98). The 5-year estimated PFS and OS from the time of the first ASCT were 17.0 and 34.9%, respectively (Fig. 1a and b). The median PFS and OS were 24 months (95% CI, 19–29) and 50 months (95% CI, 34–66), respectively. Univariate analyses were carried out using the covariates that considered age, gender, cytogenetics, the initial laboratory data (hemoglobin, calcium, creatinine, ß2-microglobulin, percentage of plasma cells in the bone marrow biopsy, Ig isotype and amount of M-protein), the response to the initial treatment, CR after the first ASCT and the number of SCT. Table 3 lists the prognostic factors found to be significant for the post- first transplant PFS and OS in multivariate analysis. The following factors were associated with a better PFS: double SCT, normal hemoglobin and low number of marrow plasma cells at the initial presentation. Double SCT, an objective response to the first SCT, female gender and an absence of advanced bone lesions were associated with an improved OS. Among these factors, the second transplant found to be the strongest factor for improving the survival. Figure 2a and b show the survivals according to the number of transplant. The median PFS was 26 months (95% CI, 23–29) in the double SCT group and 9 months (95% CI, 0–20) in the single SCT group (P = 0.005 by the log-rank test). The median OS was 60 months (95% CI, 44–76) in the double SCT group, and 36 months (95% CI, 4–68) in the single SCT group (P = 0.01 by the log-rank test). The difference in the PFS and OS according to the number of SCT (single versus double) was not significant in those patients who had obtained a CR after the first ASCT (P = 0.26 and P = 0.63, respectively). However, the difference in the PFS and OS according to the number of SCT (single versus double) was significant in those who did not obtain a CR (P = 0.0087 and P = 0.0052, respectively). There was no difference in the survival between those receiving an allogeneic and autologous SCT as the second transplant (data not shown).
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CAUSE OF DEATHS
Table 4 depicts the causes of death in each group. A total of 19 patients died of relapse/progressive disease (n = 14) or as a result of treatment-related complications (n = 5). Nine of the 17 patients (52.9%) without the second SCT died from relapse but there were no deaths due to toxicity. In the patients who received a second ASCT, 6 (25%) died from the following causes: multiorgan failure (n = 1), infection (n = 1), and relapse (n = 4). In patients with RIST as the second SCT, four patients (33.3%) died and two before day 120. The causes of death included infection (n = 1), chronic GVHD (n = 2) and relapse (n = 1). Overall, the non-relapse mortality rate was 13.9% (5/36) after the second SCT.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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This study evaluated the results of a double SCT ‘up-front’ strategy in a group of uniformly treated patients undergoing their first ASCT at a single institution (12). The vast majority of patients received the first ASCT during the first year after the diagnosis of MM and had received the same conditioning regimen (melphalan 200 mg/m2). There was no trend toward a worse performance status and a lower ORR following the first ASCT in the single transplant group. The up-front successive second SCT, regardless of the use of ASCT or RIST, improved the PFS and OS of those patients who had survived the early treatment-related mortalities after the first ASCT. Despite the non-relapse mortality (13.9%) of the second transplant, a double ASCT was more beneficial considering the high death rate (52.9%) in the relapsed patients on the maintenance treatment alone after the first ASCT.
Double-transplant regimens have been used to treat MM over the past decade, and their advantage over a single transplant was demonstrated by the French randomized IFM94 study and a single-center non-randomized comparison in which the second ASCT had been performed (6,13). Allogeneic SCT has the potential to eradicate the residual disease but the high rate of treatment-related deaths has made this treatment unacceptable to most myeloma patients (14). The markedly reduced toxicity of allogeneic SCT using non-myeloablative regimens may hold promise for more widely exploiting the well-documented graft-versus-myeloma (GVM) effect (15,16). In addition, the results of the studies investigating tandem RIST after ASCT showed a high response rate with acceptable toxic effects (4,5). The survival figures reported in this paper are in agreement with the results reported from other studies, in which the prognosis had been improved with more intensive therapy using a double SCT (3–6). Recently it has been reported that in high-risk myeloma patients the combination of ASCT followed by RIST was not superior to a tandem dose-intensified melphalan-based ASCT with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma (17).
One possible explanation for the longer duration of the PFS and OS in the double SCT group is the suppression of either the residual tumor cells or non-specific damage to the marrow microenvironment, which is necessary for tumor growth (6). In allogeneic SCT, there is a lower risk of relapse due to both the infusion of a tumor-free graft and the potential for a GVM effect mediated by the donor graft (11). Indeed, it is likely that almost all the benefits from SCT come from those patients who attain a CR (18–20). According to the experience from the University of Arkansas, 20% of complete responders are projected to remain in that state for 7 years (21). In the MD Anderson experience, the PFS and OS of 22 patients who reached a CR after HDT were longer than those of the 38 achieving only a PR (22). In line with the above results, multivariate analysis showed that the attainment of a CR after the first ASCT has a significant positive effect on the OS (P = 0.001). However, in case of PFS, there was no difference between the patients with or without a CR (P = 0.255). The disparate influence of a CR on the gain in OS and PFS might occur because a double SCT can improve the PFS in patients who did not achieve a CR after the first ASCT (P = 0.0087). These results are in agreement with the report showing that the benefit of a double SCT might depend on the response status after the first ASCT (23).
Double autografting resulted in a median PFS of 30–43 months and an OS of between 58 and 68 months (6,19,24). A third of patients may live for 10 years (25). For the single- and double-transplant groups of patients, the median PFS was 9 (95% CI, 0–20) and 26 (95% CI, 23–29) months (P = 0.005), and the median OS was 36 (95% CI, 4–68) and 60 (95% CI, 44–76) months (P = 0.01), respectively (Fig. 2). The higher proportion (92.4%) of stage III patients in this study could be the reason for the lower rate of PFS and OS compared with other results. In addition to the up-front second SCT, multivariate analysis in this small group of patients demonstrated the importance of the response to the first ASCT, the number of osteolytic lesions and bone plasma cells, hemoglobin and female gender. The high number of bone marrow plasma cells and the low hemoglobin levels indicate a shorter PFS (26). It was reported that patients obtaining a CR after the first ASCT had the best OS (27). A poor prognosis has also been linked to the detection of abnormal metaphases, such as hypodiploidy and deletions 13 (28). In this study, genetic changes were not associated with the OS and PFS probably because the proportion of patients with a cytogenetic abnormality was small.
The optimal timing of the second transplant is still an open question, i.e. whether to use it up-front or later as a rescue treatment, because an SCT will always be a risk factor for treatment-related death. In order to improve the survival of a double SCT, the second SCT should be performed before relapse and within 6–12 months after the first ASCT (12). The options for relapsed post-SCT patients are limited, and their long-term efficacy remains unanswered. This is despite the fact that newly introduced agents, in particular thalidomide and bortezomib alone or in combination with steroids or reduced doses of cytotoxic agents, are likely to be an effective treatment option for refractory patients with MM, including post-SCT relapse patients (29–31). Since the second ASCT or RIST were relatively safe and well tolerated in our patients, it is better to perform the second SCT within a limited period as a consolidation treatment rather than as a salvage therapy after relapse. Further randomized protocols will be needed to clarify the role of a double SCT in MM.
Although there was no trend toward a worse performance status in the single transplant group, there might be some biases that they had a poorer clinical background. Most of them did not receive the tandem transplant because of a financial problem. In addition, only two patients received an effective maintenance treatment with thalidomide. Recently the analysis of the IFM99 02 trial strongly suggested that thalidomide is an effective maintenance treatment after high-dose therapy for myeloma (32).
Three out of four relapsing patients (75%) after RIST developed extramedullary plasmacytomas while their BM was in remission. Therefore, it can be postulated that circulating allogeneic T cells may not reach or may not bind to plasma cells in the soft tissues efficiently or that the microenvironment may secrete cytokines suppressing T cell function (33,34). New approaches are needed to deal with the problem of extramedullary disease recurrence after transplant. Recently, it has been shown that bortezomib, the proteasome inhibitor, has an extensive tissue penetration on soft-tissue masses (35).
In summary, this non-randomized comparison between a single and double SCT as an up-front treatment shows that the second SCT, either ASCT or RIST, tends to improve the PFS and OS among patients with MM who successfully received their first ASCT. The survival benefit was comparable between the second ASCT and RIST. Based on this and other reports, an up-front double SCT is recommended as an initial treatment for MM patients (3–6).
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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